rs201715603

chr1-11989226-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_014874.4(MFN2):c.58C>T(p.His20Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,614,124 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (9 hom.)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 3.78

Genes affected

MFN2 (HGNC:16877): (mitofusin 2) This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MFN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.33870715).
• BP6: Variant 1-11989226-C-T is Benign according to our data. Variant chr1-11989226-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214656.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=2}. Variant chr1-11989226-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFN2	NM_014874.4	c.58C>T	p.His20Tyr	missense_variant	3/19	ENST00000235329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFN2	ENST00000235329.10	c.58C>T	p.His20Tyr	missense_variant	3/19	1	NM_014874.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000755 AC: 19 AN: 251490 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461888 Hom.: 9 Cov.: 31 AF XY: 0.000122 AC XY: 89 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

Charcot-Marie-Tooth disease type 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 20 of the MFN2 protein (p.His20Tyr). This variant is present in population databases (rs201715603, gnomAD 0.01%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 24957169, 31453851). ClinVar contains an entry for this variant (Variation ID: 214656). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2020	This variant is associated with the following publications: (PMID: 27884173, 31453851, 24957169) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	MFN2: PP3 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2020

The p.H20Y variant (also known as c.58C>T), located in coding exon 1 of the MFN2 gene, results from a C to T substitution at nucleotide position 58. The histidine at codon 20 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This alteration has been reported in a compound heterozygous state together with MFN c.2218T>A (p.Trp740Arg) in an individual with CMT2A (Al-Harbi TM et al. J Clin Neuromuscul Dis, 2019 Sep;21:25-29), as well as in a heterozygous state in an individual with CMT (Bombelli F et al. JAMA Neurol, 2014 Aug;71:1036-42). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary motor and sensory neuropathy with optic atrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.0015	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	21
Dann	Benign	0.82
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.90	L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.98	N;N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.44	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.014	B;B;.
Vest4		0.61
MVP		0.69
MPC		0.86
ClinPred		0.032	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201715603; hg19: chr1-12049283;